This invention relates to measuring severity of periodontal and peri-implant disease.
Periodontal and peri-implant disease activity presently are diagnosed by clinical parameters such as pocket depth, bleeding on probing, and radiographs. These parameters have limitations in that they lack ability to predict future attachment loss, and provide information only on the existence of past disease activity. The need for diagnostics in periodontology which are predictive markers of active periodontitis is a focus of present research.
Periodontal disease is a general term used to describe specific diseases that affect the gingiva, as well as the supporting connective tissues and alveolar bone which anchor the teeth in the jaws. The periodontal diseases are among the most common infectious diseases in humans. In the last fifteen years, with the decline of dental caries in children aged 6-18, and better prevention programs for the general population, periodontal disease leading to tooth loss has assumed even greater importance. As more teeth are retained due to reduced caries, more teeth are at risk to be affected by periodontal disease (Shaw, J. H., N. Eng. J. Med. (1987) 317:996; Williams, R. C., N. Eng. J. Med. (1990) 332:373). Thus, the recognition and diagnosis of periodontal disease has become even more important.
The use of clinical parameters for the diagnosis of periodontal disease has numerous limitations. For example, Haffajee and co-workers (Haffajee, A. D., et al., J. Periodontal (1991) 18:117) have demonstrated that no clinical parameters have been shown to be predictive for periodontal disease activity. Thus there have been intensive research efforts to develop diagnostic tests for periodontal disease evaluation. Over 40 different tests for gingival crevicular fluid (GCF) components have been studied, e.g., collagenase (Villela, B. et al., J. Periodont. Res. (1987) 22:264), alkaline phosphatase (Ishikawa, I. et al., Arch. Oral. Biol., (1970) 15:1401; Binder, T. A. et al., J. Periodont. Res. (1987) 22:14), cathepsin-like activities (Kunimatsu, K. et al., J. Periodont. Res. (1990) 25:69; Cox, S. W. et al., J. Periodont. Res. (1989) 24:353; Cox, S. W. et al., J. Periodont. Res. (1989) 24:41; Beighton, D. and Life, J. S. C., Arch Oral. Biol. (1989) 34:843), and .beta.-glucuronidase (Lamster I. B. et al., J. Periodontol. (1985) 56:139).
Despite the plethora of such components, there are at present no diagnostic tests available which have been demonstrated to be highly predictive for future bone and attachment loss in periodontal disease. As the breakdown of these components is the ultimate concern of the practitioner, their destruction should be evaluated. Connective tissue-associated proteins such as glycosaminoglycans (Giannobile, W. V. et al., J. Periodontol. (1993) 64:186) and osteonectin (Bowers, M. R. et al., J. Periodontol (1989) 60:448) have been found in GCF from patients exhibiting clinical signs of periodontitis. However, no longitudinal studies have been performed which relate these components to future bone or attachment loss.
Collagen makes up approximately 90% of the organic matrix of bone. Collagen type I is the most abundant collagen of osseous tissues (Deftos, L. J., Clin. Chem. (1991) 3/7:1143). Following procollagen biosynthesis and its release into the maturing extracellular matrix, collagen molecules form crosslinks which provide additional mechanical stability to the matrix (Miyahara, M. et al., J. Biol. Chem. (19082) 257:8442). These intermolecular crosslinks are formed between the terminal, nonhelical telopeptide regions on one collagen molecule and the helical parts or another chain. The resultant crosslinks are initially bivalent, which in turn become multivalent complexes with collagen matrix maturation (Last, J. A. et al., Int. J. Biochem. (1990) 22:559). Crosslink biosynthesis is initiated by lysine and hydroxylysine residues. There are two major types of crosslinks: (1) Enzyme lysyl oxidase initiated crosslinks, and (2) derivatives from nonenzymatically glycosylated lysine and hydroxylysine residues. Pyridinoline crosslinked carboxy terminal telopeptide of type I collagen (ICTP) are derived from the carboxyterminal telopeptide regions of type I collagen which has been cross-linked via pyridinoline. ICTP is liberated during the degradation of type I collagen. ICTP is found in an immunochemically intact form in blood, where it appears to be derived from bone resorption. ICTP crosslinked compound contains three peptides, the principal one of which is the carboxyterminal telopeptide of the .alpha.1(I) chain, which is considerably smaller than the ICTP peptide determined from SDS-PAGE (Risteli, J. et al., Clin. Chem. (1993), 39:635).
Collagen also serves as precursor for another class of pyridinoline crosslinked compound: cross-linked N-telopeptides of type I collagen (NTP) (found on the N-terminal end of the original collagen type I molecule), hydroxylysylpyridinoline, (pyridinoline or HP) and lysylpyridinoline (deoxypyridinoline or LP) which are measurable in urine (Seyedin S. M. et al., J. Bone Miner. Res. (1993), 8:635; Gertz, B. J. et al., J. Bone Miner. Res. (1994), 9:135; Eriksen, E. F. et al. (1993), J. Bone Miner. Res., 8:127). These molecules, produced from the degradation of type I collagen (ICTP, NTP, HP and LP), are termed "Pyridinoline Crosslinks".
Changes in serum concentrations of ICTP crosslinked compound have been observed in some metabolic bone diseases where it correlates with the bone resorption rate measured either histomorphometrically or by calcium kinetic studies (Eriksen, E. F. et al., J. Bone Miner. Res. (1993), 8:127;Hassager, C. et al., Bone Miner. Res., (1992), 7:1307). Serum ICTP crosslinked compound also correlate with the urinary excretion of ICTP crosslinked compound, as measured by HPLC (Robins, S. P., Biochem. J. (19082), 207:617).
Increased serum concentrations of ICTP crosslinked compound are seen in conditions associated with increased lysis of bone, such as multiple myeloma, osteolytic metastases, rheumatoid arthritis, and immobilization (Elomaa, I. et al., Br. J. Cancer, (1992), 66:337). In addition, studies have shown that in postmenopausal women, estrogen treatment decreases serum ICTP crosslink concentrations.